The phosphodiesterase inhibitor compounds are the main agents used in clinical medicine for treatment and/or prevention of erectile dysfunction, disorders and/or treatable conditions with tissues relaxation and other diseases treatable with phosphodiesterase inhibitors. In the case of erectile dysfunction, PDE-5 inhibitors are the most widely used in clinical medicine.
Erectile dysfunction, more commonly known as sexual impotence is one of the diseases that most affect a man's quality of life. For a long time, erectile dysfunction haunted men without considerable chances for effective treatment.
Before the 1970s, almost all cases of erectile dysfunction were considered resulting from psychological causes, and treatments consisted of empirical administration of testosterone or referral to a psychiatrist. The development of new treatments such as inflatable penile prostheses, developed in 1973 and the emergence of intracavernous injections, in early 1980, were important milestones in the history of modern erectile dysfunction treatments. The first treatment of oral use, based on sildenafil citrate (Viagra's active ingredient) was released in 1998 and was an important milestone for erectile dysfunction treatments.
Oral treatment is more accepted by men, developed through clinical research on the use of cGMP-PDE inhibitors, more particularly PDE-5 inhibitors. The precursor of these compounds was 5-{2-Ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-propyl-1,4-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or sildenafil, with vasodilating properties, and which enhances the nitric oxide effects. The Sildenafil molecule was originally described in U.S. Pat. No. 5,250,534.
Later, other inhibitor compounds of the enzyme PDE-5 were developed and are cited in a number of technical literature publications, as well as in patent publications. Among the known compounds include: the molecule of vardenafil, Levitra's active ingredient, first described in the U.S. Pat. No. 3,635,178; tadalafil, Cialis's active ingredient, first described in U.S. Pat. No. 5,859,006; and the compound BL-106, not yet commercialized, first described in U.S. Pat. No. 8,338,432 and developed by the same team of present invention's researchers.
Available studies report that some form of sexual dysfunction affects 10-52% of men. The study by Feldman and his colleagues have shown that 52% of men between the ages of 40 and have mild, moderate and severe degrees of erectile dysfunction. Between the ages of 40 and 70, the prevalence of mild erectile dysfunction remains relatively constant, but the prevalence of moderate to severe erectile dysfunction increases with each decade with the total combined increase progressing from 40% at age 40 years to almost 70% at 70 years (Feldman H A, Goldstein I, Hatzichristou D G, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61).
Additionally, the researchers found that tissue relaxing compounds have been used to promote relaxation of various tissues with a focus on treating or acting as an aid in the treatment, procedure or related surgery of gallstones (Korkes, F. et al, J Bras Nefrol. (2009) 31 (1): 55), increased prostate (e.g., benign prostatic hyperplasia, prostatitis) (WO 9911279) and urethral constriction (Van der Werf et al BJU International (2002) 90: 588). Other disorders and/or conditions treatable with tissue relaxation are known and described in the art.
PDE-5 inhibitors have been used to block the degradation of cGMP to prolong nitric oxide (NO) effects in various tissues, for example, to maintain the NO-induced relaxation in airways and blood vessels (Barnes, P J, et al., (1995) and to maintain the NO-induced protection in tissue (Duffin, R., et al., Br J Pharmacol. (2008) 153(4): 623. Such actions in the tissues are shown to be beneficial for the treatment of several disorders—disorders which are treatable with inhibitors of phosphodiesterases, particularly PDE-5, including pulmonary hypertension (commercially treated with sildenafil citrate); bronchitis; chronic asthma; hypertension (EP758653,U.S. Pat. No. 7,569,572); Raynaud's disease (Ghofrani H A et al, Nat Rev Drug Discov 2006; 5:689); the onset of right-sided heart failure (Ghofrani et al. (2003) AJRCCM 167 (8): 1139); neurogenesis and functional recovery post stroke (Zhang et al. (2002) Stroke 33: 2675-2680); coronary artery relaxation (Halcox et al. (2002) J Am Coll Cardiol 40: 1232); disorders of female sexual arousal (Nehra et al. (2001) World J Urol. 19 (1): 115); angina and congestive heart failure (Reffelmann et al., Circ. (2003) 108(2):239). Other disorders treatable with PDE-5 inhibitors are known and described in the art.
Within this framework and seeking new alternatives of phosphodiesterase inhibitor compounds, more specifically as PDE-5 inhibitors, new treatments for erectile dysfunction, disorders and/or conditions treatable with tissues relaxation and other diseases treatable with phosphodiesterase inhibitors, the present invention's researchers have developed new compounds derived from 6,7-dihydro-3H-oxazolo[3,4-a]pyrazine-5,8-dione, object of the present invention, which present enzymes' phosphodiesterase inhibitory activity, including inhibition of PDE-5.